Aggrecan degradation and subsequent digestion of collagen fibrils are the central pathway for the destruction of cartilage in human joint diseases including osteoarthritis (OA) and rheumatoid arthritis (RA). Collagen degradation is carried out principally by collagen-degrading matrix metalloproteinases (MMPs) such as MMP-1, MMP-8 and MMP-13 [1-3]. On the other hand, aggrecan-degrading metalloproteinases called aggrecanases are considered to play a key role in the aggrecan degradation [4, 5]. Aggrecanases belong to the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) gene family, and ADAMTS1, 4, 5, 8, 9 and 15 are known to have aggrecanase activity [4, 6]. Recent studies using ADAMTS4 and ADAMTS5 knockout mice have indicated that ADAMTS5, but not ADAMTS4, plays an essential role in aggrecan degradation in mouse arthritides [7, 8]. However, because there is little information about the biochemical character, expression patterns or gene promoter structures of mouse ADAMTS4 and ADAMTS5, the data from knockout mice must be interpreted carefully and should not be extrapolated to the human disease OA and RA [9, 10]. In human chondrocytes, ADAMTS4 is inducible by treatment with cytokines such as interleukin-1 (IL-1), but the expression of ADAMTS5 is constitutive [9, 11-13]. Our recent study also showed that among aggrecanase-type ADAMTS species, ADAMTS4 is selectively overexpressed in human osteoarthritic cartilage with a direct correlation to the degree of cartilage destruction, while ADAMTS5 is constitutively expressed in both normal and osteoarthritic cartilage [10]. These suggest that ADAMTS4 is a major aggrecanase in human osteoarthritic cartilage. ADAMTS4 is also overexpressed by synovial cells and articular chondrocytes in RA, suggesting the involvement of this proteinase in cartilage destruction of RA joints. ADAMTS4 and ADAMTS5 can digest not only aggrecan but also other members of the proteoglycan lectican family including versican and brevican. Since versican is a major proteoglycan in the skin and blood vessel wall, its degradation by ADAMTS4 and ADAMTS5 is also implicated in tissue destruction and repair of the skin and blood vessels under pathological conditions such as chronic ulcer and fibrosis of the skin and various vasculitides, respectively. In addition, tumor cells in glioblastoma multiforme are known to overexpress ADAMTS5 and tumor cell-derived ADAMTS5 is suggested to play a role in invasion by cleavage of brevican [14].
The phage display method is one of the display techniques that have realized an in vitro high-speed selection by forming a one-to-one correspondence in the form of phage particle between a functional peptide or protein and a DNA encoding same. This phage display method is applied to antibody selection, and many antibodies obtained by this method have been developed as pharmaceutical products [15]. Furthermore, a method of obtaining a specific antibody by a combination of a human artificial antibody library and a phage display method has been established, and such methods have been practicalized by plural companies, as evidenced by HuCAL (Human Combinatorial Antibody Library) of MorphoSys.